Our results during the last funding period indicate that activation of renovascular Y1 receptors (Y1Rs) dramatically enhances renovascular responses to physiological levels of angiotensin II (Ang II) in kidneys of spontaneously hypertensive rats (SHR). However, Y1Rs have little effect on Ang ll-induced responses in kidneys of normotensive Wistar-Kyoto rats (WKY). In stark contrast, activation of Y2 receptors (Y2Rs) has, at most, only a minor effect on renovascular responses to Ang II in SHR kidneys, with no effect whatsoever in WKY kidneys. These data indicate that endogenous agonists of Y1 Rs, but not Y2Rs, would potentiate Ang ll-induced renal vasoconstriction in genetically-susceptible kidneys, provided these endogenous agonists could reach the renal microcirculation. Are there endogenous agonists of Y1 Rs that could activate Y1Rs in the kidney microcirculation? The answer is yes. A fatty meal releases peptide YY1-36 (PYY1-36) into the systemic circulation from endocrine L-cells in the small bowel, colon and rectum producing physiologically active levels of PYY1-36 in plasma that are 500% to 1000% above basal circulating levels, and this circulating PYY1-36 would be delivered promptly to the renal microcirculation via the blood stream (humoral input to kidney microcirculation). Renal sympathetic nerves release neuropeptide Y1-36 (NPY1- 36) in response to CNS-mediated activation of renal sympathetic nerves (neural input to kidney microcirculation), resulting in high local levels of NPY1-36 in sympathetically-innervated renal microvessels during renal sympathetic activation. Because both PYY1-36 and NPY1-36 are potent Y1R agonists, physiological processes that increase PYY1-36 release from the gut, NPY1-36 release from renal sympathetic nerves or both simultaneously would activate Y1Rs in the renal microcirculation, which in genetically-susceptible kidneys would enhance Ang ll-induced renal vasoconstriction. It is conceivable, however, that stimulation of Y1Rs by physiological processes that increase the exposure of the renal microcirculation to PYY1-36 and NPY1-36 is diminished by the activity of vascular dipeptidyl peptidase IV (DPP IV) residing in the walls of blood vessels that comprise the renal microcirculation. DPP IV converts PYY1-36 to PYY3-36 and NPY1-36 to NPY3-36 by cleaving two amino acids from the N-terminus of either PYY1-36 or NPY1-36. Whereas PYY1-36 and NPY1-36 are potent Y1R agonists, PYY3-36 and NPY3-36 are inactive at Y1Rs but are potent and selective Y2R agonists. These facts suggest the hypothesis that DPP IV in the renal vasculature is a critical determinant of the extent to which PYY1-36 and NPY1-36 enhance renovascular responses to Ang II in genetically-susceptible kidneys. The testing of this hypothesis is the focus of this application. The proposed hypothesis is absolutely novel. The concept that DPP IV exists in the renal vasculature and regulates renal blood flow has never been proposed or tested.